Tumor metastasis is the main cause of death from cancer and a major challenge for improving cancer management. Hematogenous tumor cell spreading is a highly complex process, including detachment of cancer cells from the primary site, migration into and transport along the bloodstream, and finally tumor cell arrest and proliferation within distant tissue. Thus survival of tumor cells within the bloodstream and adhesion in the vasculature at the metastatic site are crucial for tumor cell dissemination. Extensive evidence indicates that the interaction of tumor cells with platelets within the bloodstream plays an important role during the early phase of metastasis. (Gay et al., “Contribution of Platelets to Tumour Metastasis,” Nat. Rev. Cancer. 11(2):123-134 (2011); Labelle et al., “Direct Signaling Between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis,” Cancer Cell 20(5):576-590 (2011)).
The involvement of platelets and coagulation factors in hematogenous tumor metastasis has long been recognized. Cancer patients frequently present with signs of thrombosis, and these are most severe if the disease has progressed to a metastatic stage (Gay et al., “Contribution of Platelets to Tumour Metastasis,” Nat. Rev. Cancer. 11(2):123-134 (2011); Labelle et al., “Direct Signaling Between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis,” Cancer Cell 20(5):576-590 (2011); Tomita et al., “Prognostic Impact of Thrombocytosis in Resectable Non-Small Cell Lung Cancer,” Interact. Cardiovasc. Thorac. Surg. 7(4):613-615 (2008); Suppiah et al., “Thrombocytosis as a Prognostic Factor for Survival in Patients with Metastatic Renal Cell Carcinoma,” Cancer 107(8):1793-1800 (2006); Ayhan et al., “The Value of Preoperative Platelet Count in the Prediction of Cervical Involvement and Poor Prognostic Variable in Patients with Endometrial Carcinoma,” Gynecol. Oncol. 103(3):902-905 (2006); Shimada et al., “Thrombocytosis Associated with Poor Prognosis in Patients with Esophageal Carcinoma,” J. Am. Coll. Surg. 198(5):737-741 (2004); Borsig, L., “The Role of Platelet Activation in Tumor Metastasis,” Expert Rev. Anticancer Ther. 8(8):1247-1255 (2008)). Furthermore, thrombocytopenia or the inhibition of platelet function can markedly suppress tumor metastasis (Francis et al., “Effect of Antihemostatic Agents on Experimental Tumor Dissemination,” Semin. Thromb. Hemost. 28(1):29-38 (2002); Amirkhosravi et al., “Blockage of GPIIb/IIIa Inhibits the Release of Vascular Endothelial Growth Factor (VEGF) From Tumor Cell-Activated Platelets and Experimental Metastasis,” Platelets 10(5):285-292 (1999); Troxler et al., “Platelet Function and Antiplatelet Therapy,” Br. J. Surg. 94(6):674-682 (2007); Rothwell et al., “Effect of Daily Aspirin on Risk of Cancer Metastasis: A Study of Incident Cancers During Randomized Controlled Trials,” Lancet 379(9826):1591-1601 (2012)). Subsequent animal models in which specific platelet functions were altered through drug treatment or controlled genetic ablation have led to a model of platelet supported tumor metastasis in which tumor cells enter the bloodstream (intravasation), and bind and activate platelets (cohesion) and leukocytes (Sierko et al., “Inhibition of Platelet Function: Does it Offer a Chance of Better Cancer Progression Control?” Semin. Thromb. Hemost. 33(7):712-721 (2007); Trikha et al., “Role of AlphaII(b)beta3 Integrin in Prostate Cancer Metastasis,” Prostate 35(3):185-192 (1998)). These host cells then assist tumour cell arrest at the vessel wall (adhesion) and survival within the vasculature (immune evasion), which enables exit from the circulation (extravasation), and tumour cell survival and proliferation within target tissues of metastasis (Jain et al., “Platelet Glycoprotein Ib (alpha) Supports Experimental Lung Metastasis,” Proc. Natl. Acad. Sci. U.S.A. 104(21):9024-9028 (2007); Nieswandt et al., “Lysis of Tumor Cells by Natural Killer Cells in Mice is Impeded by Platelets,” Cancer Res. 59(6):1295-1300 (1999); Palumbo et al., “Platelets and Fibrinogen Increase Metastatic Potential by Impeding Natural Killer Cell-Mediated Elimination of Tumor Cells,” Blood 105(1):178-185 (2005)). These contributions of platelets to tumour cell survival and spread suggest that agents directed against these processes may give rise to new therapies for patients with a high risk of metastasis or for minimizing the risk of cancer cell dissemination during tumor surgery.
The present invention is directed at overcoming this and other deficiencies in the art.